1. Technical Field of the Invention
The present invention relates to the field of diagnostic imaging. More specifically, the invention involves improved imaging of tissue sites of inflammation. Improved diagnostic images result from an increase in the number of labeled leukocytes in the area of the inflammation or from improved selectivity of antibodies or peptides for activated leukocytes in sites of inflammation versus non-activated leukocytes in the circulation.
2. Background Art
Inflammation occurs as a result of infection with a microorganism, tissue injury, or, as has been recently recognized, in non-apparent tissue injury associated with transient ischemia. A major application of imaging agents targeted to inflammation has been the imaging of abscesses due to regional replication of microorganisms.
Two general methodologies have been developed for imaging abscesses caused by replication of infectious organisms like bacteria or fungi. The first relies on detection of antigens expressed by the bacteria or fungi. In this case, antigen expressed by the microorganism itself is the target for imaging by antibody. The second method makes use of the fact that growth of infectious organisms will cause inflammation. The inflammation process then can be used as a target for imaging.
The most utilized method for imaging inflammation is one in which polymorphonuclear leukocytes (PMNs) or unfractionated leukocytes are isolated from a patient and labeled with radionuclides (for instance, with .sup.111 In). The labeled autologous leukocytes are then reinjected into the donor. A certain percentage of the labeled PMNs will accumulate at the sites of abscess formation or inflammation. However, many drawbacks have been experienced using this methodology. One such difficulty relates to the labeling methodologies and their effect on leukocyte trafficking. Oxidative processes used in the labeling procedure may cause the PMNs to be more effectively removed by the reticuloendothelial system (RES) which has as its normal function the recognition, removal and destruction of effete cells in the body. Thus, in scans obtained by such labeling methodologies a substantial accumulation of labeled cells in the liver, spleen, and other RES sites is commonly observed. This RES accumulation detracts from a diagnostician's ability to detect inflammatory lesions within RES organs. Such accumulation also reduces the number of labeled cells that can accumulate at the site of the abscess (bioavailability), and thus decreases the sensitivity of inflammation detection in organs outside of the RES.
One abscess imaging methodology which has been suggested as an improvement involves a non-oxidative method of labeling the cells, making use of radiolabeled antibodies which bind to surface antigens of PMNs. Antibodies are labeled with a radioisotope suitable for imaging, and the antibody is then incubated with isolated PMNs or leukocytes prior to reinjection of the autologous cells into the donor. The method is an improvement because of its simplicity, but might also improve the number of leukocytes that can localize to abscesses because of reduced labeled cell accumulation in the RES system. Even with this improvement, only a small percentage of the labeled leukocytes will actually localize to the tissue sites of inflammation. Thus, there is a need for improved methods for enhancing accumulation of labeled leukocytes, and more specifically PMNs, into abscesses and sites of tissue inflammation.
Other potential methods for imaging abscesses or sites of inflammation use passively administered antibodies to localize to sites of inflammation. Such uses have been postulated for monoclonal antibodies directed to activation antigens expressed on monocytes which have matured into macrophages.